1,000 Shades of Blue

1,000 Shades of Blue

Depression has many faces, and — through its Grand Challenge — UCLA is learning to recognize them all.

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Lyndon Stambler | April 1, 2020

Tamar Kodish M.A. ’17, a certified coach in UCLA’s Screening and Treatment for Anxiety & Depression (STAND) Program, has seen many facets of depression.

In one crisis, Kodish helped a student who had been sexually assaulted at a party. She revealed on an online tracker that she was ashamed and thought about dying. But she had no suicide plan, lowering the immediate risk. Kodish helped her develop a “safety plan” — including finding coping strategies and establishing a network of supportive people — and quickly made an appointment for her with a psychotherapist at the STAND-affiliated Innovative Treatment Network Clinic.

Then there was the community college transfer student who felt overwhelmed by his academic workload. He had lost interest in things he’d once enjoyed — a condition called anhedonia. STAND used digital therapy modules in combination with a certified coach to engage the student in positive activities, a technique called behavioral activation. As a result, he got out of his dorm room and developed a more positive outlook.

“Depression looks different for different people,” says Kodish, a clinical psychology graduate student. Along with more than 100 faculty luminaries, staff and students, Kodish is part of UCLA’s Depression Grand Challenge (DGC), which aims to cut the global burden of depression in half by the end of the century.

“We’ve had to intervene because people say, ‘I want to kill myself, and I have the means to do it,’” says Michelle G. Craske, distinguished professor and director of ITN. “We’ve taken them to the ER. I believe we have prevented suicides.”

According to the World Health Organization, nearly 800,000 people die by suicide every year. Although the global suicide rate has declined by nearly a third since 1990, it is on the rise across the U.S., according to the Centers for Disease Control and Prevention, and it’s particularly striking among young people. Suicide is the 10th leading cause of death in the U.S., claiming nearly 45,000 lives a year, with another quarter of a million people left behind as “suicide survivors.” These figures underscore how vital it is to understand the causes of depression and to improve diagnoses and treatment. Since November 2017, STAND has responded to more than 1,000 alerts for suicide emergencies or severe depression.

To that end, the DGC views depression as not one condition, but many — from depression that is early onset, postpartum and late-life, to depression that is stress related or associated with medical conditions, substance abuse or anxiety. It varies across genders and cultures, changing over time. But only 50% of those with depression get treatment, and of those, only half return to full mental health. Why? “Existing treatments are simply not effective enough, especially when we are not matching treatments to each person’s needs,” Craske says.

Nelson B. Freimer, director of the DGC and distinguished professor of psychiatry and biobehavioral sciences at the David Geffen School of Medicine at UCLA, agrees. “Although we might call depression by one word, there will be important differences in terms of the course of illness and treatments,” he says. “Because depression often manifests as something that goes awry in the way the brain relates to the rest of the body, we are interested in what depression looks like in [people with] cancer, stroke, diabetes and heart disease and women who have given birth.”

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Imbalances in Humors

Depression is a profound state of sadness, shame, guilt, worthlessness and hopelessness that can last weeks, months and even years. Symptoms include difficulty sleeping, eating and concentrating; low energy; and feelings of poor self-worth. It increases the risk and worsens the course of heart disease, cancer, stroke and other diseases.

The American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders lists nine symptoms of major depressive disorder. But one study says there are 1,000 unique combinations of symptoms, or 1,000 shades of blue.

“One person might have increases in sleep and weight gain,” says Zachary Cohen, a postdoctoral fellow who came to UCLA to work under Craske on the DGC Tech Suite for Online Therapy, which he describes as a “dream project.” “Another person might have decreases in sleep and weight loss. Another might have no changes in sleep and weight but have difficulties concentrating. There are so many combinations [that] it is unlikely there is one thing that is depression.”

The ancient Greeks believed imbalances in humors, or biles, were responsible for depression. The word “melancholia” comes from melaina chole, or “black bile.” Abraham Lincoln, Winston Churchill and Robin Williams have suffered from it. About 17 million U.S. adults will experience depression each year. It’s the most common cause of disability worldwide, affecting more than 322 million people at any time. And yet, Freimer says, “We don’t understand depression well.”

In 2015, UCLA created the DGC “to better understand, diagnose and treat depression. What has evolved is our understanding of how we’re going to get there,” says Michelle Popowitz ’91, J.D., M.P.H. ’97, assistant vice chancellor for research and co-founder of UCLA Grand Challenges.

The DGC has four components: Innovative Treatment Network, Causes and Trajectories, Discovery Neuroscience, and Awareness and Hope.

STAND, which was developed under the ITN component, uses Computerized Adaptive Testing for Mental Health to place participants into one of four tiers.

Tier Zero is for people without symptoms, who are monitored for prevention. Tier One is for people with mild depression and anxiety, who receive digital therapy through smartphones and guidance from trained, certified coaches in the Resilience Peer Network. Tier Two focuses on moderate depression to severe anxiety, with participants receiving digital therapy and coaching from more advanced certified coaches. People in Tier Three receive psychotherapy (with or without antidepressant medication) from advanced graduate students, postdoctoral fellows and psychiatry residents — supervised by licensed clinicians. To make this approach more scalable, the DGC plans to utilize the expertise of nurses and social workers, under supervision, to provide the Tier Three treatment. Since 2017, STAND has screened 7,000 students and has offered treatment to more than 3,000.

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A Better Understanding

This April, the DGC will introduce a suite of digital treatments — STAND Digital Cognitive Behavioral Therapy — at UCLA, then at East L.A. College in August. “STAND is designed to be a scalable system of care that we envision being able to put in a box and export to other settings,” Popowitz says. “That’s incredible.”

Cohen and other members of Craske’s team developed more than 24 digital modules in a lab staffed by voice actors, animators, scriptwriters, graphic designers and engineers. “Most of our voice actors are on [the Internet Movie Database]. It’s not typical academia,” he says.

The goal is to augment, not replace, face-to-face care. “We cannot make a big dent in the total burden of mental illness if we rely only on face-to-face delivery of cognitive behavioral therapy,” Cohen says. “We can’t train enough people.”

“If someone comes in with depression, we’ve got a set of modules that address the different parts of depression,” Cohen says. “If someone comes in with sleep problems, they’ll get modules that each target different aspects of sleep regulation. We can improve outcomes simply by matching people to the right treatment components.”

“Existing treatments are simply not effective enough, especially when we are not matching treatments to each person’s needs.”

Michelle G. Craske

Distinguished professor and director of Innovative Treatment Network

Cohen, who moved from Colorado specifically to work on the DGC, adds, “It’s like nothing else I’ve seen in psychology. The potential impact is enormous. It could actually make a difference.” The team has also incorporated Craske’s approach for treating anhedonia, which affects 33% of people with depression.

Craske recently published studies demonstrating the effectiveness of a regimen in which patients schedule daily pleasurable events, learn to attend to and savor positive experiences and practice exercises such as acts of kindness to promote positive emotions.

Patients also use virtual reality to witness pleasurable scenes that they can mentally retrieve later. “In the past, we had nothing that worked for anhedonia,” Craske says. “Now we have something. We’ll keep moving forward and get better at targeting the right thing for the right person at the right time.”

Within the DGC umbrella, ITN is tightly integrated with the Causes and Trajectories component, which is headed by Jonathan Flint, professor-in-residence of psychiatry and biobehavioral sciences at the Geffen School of Medicine. Flint conducted the largest genetic study of depression so far, sequencing the genomes of 10,000 Han Chinese women and identifying two loci for major depressive disorder.

In 2015, Flint moved to UCLA from the University of Oxford, partly because of the DGC’s plans to recruit a cohort of 100,000 people for the Causes and Trajectories component, which includes the goal of sequencing their genomes in order to identify the causes of depression. He and Freimer remain dedicated to that goal. “The starting point is to improve treatment through a better understanding of the origins of the disease,” Flint says. “If we don’t have that, we don’t have a leg to stand on.”

They’re also seeking greater understanding of postpartum depression, working with Geffen School of Medicine’s Department of Obstetrics and Gynecology on a study that will track women from their first prenatal visit until a year after they’ve given birth. “Deploying the technology that we’ve developed through STAND means not only [will] we be able to detect [postpartum depression] earlier, but maybe before the woman herself knows that she’s depressed,” Flint says.

Women showing symptoms will receive care through the ITN Clinic. “If we identify women who are at risk early, that will help them, and it will also help prevent the negative effects cascading down to the infant,” Craske says.

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Window Into Darkness

The Causes and Trajectories component is conducting a behavioral health tracking and depression study in which participants’ phones have an app that monitors social contacts, physical activity and sleep. Also, using voice recordings from his China study, Flint has analyzed voice patterns of women with depression, theorizing he can diagnose depression based on voices alone. “In a minute’s worth of recording, we might extract 800 pieces of information,” says Flint, whose team has identified clusters that are possibly correlated with depression and suicidality.

“The recordings give us real-time data and a multidimensional quality,” he says. “If I interrogate someone, and I get that they were lonely, had poor sleep, bad appetite and concentration, I might get four symptoms. Now I’m getting 300 to 400 bits of information on your activity level, a similar amount from your voice, accelerometer, contacts and sleep patterns. The information we’re collecting is mounting up, giving us ideas about how we can divide it.”

The data provide a window into darkness. “We can measure your mood as it is now, just from looking at the behavior recorded by your phone,” Flint says. “And we are looking at how well it predicts your future mood.

“We’re beginning to understand which bits of information will be predictive of mood, and we know how to treat people who show signs of needing it. Our next question is, how do we move forward with our main objective: understanding the causes of depression and treating it everywhere?” Yes, everywhere. Flint has negotiated with Taiwan and other East Asian countries about exporting STAND.

Freimer, who has worked extensively in Latin America, is recruiting 10,000 people in Colombia for a study of brain functions and genetics, looking for patterns of depression in relation to bipolar disorder and other forms of mental illness. Funded by the National Institute of Mental Health, the study could expand to 50,000 people with a severe mental illness and 50,000 volunteers who do not have a mental illness as a control group.

Eliza Congdon, assistant professor of psychiatry at the Geffen School of Medicine and project director of the studies within the underlying Causes and Trajectories component, monitors the widening array of approaches at the DGC, from behavioral tracking to STAND, postpartum depression and sequencing the genomes of 100,000 people. “I’m in the forest, living among the trees,” she says.

Congdon is also a co-investigator in a Discovery Neuroscience study, which is aimed at assessing neurobiological changes in response to three fast-acting treatments: the anesthetic ketamine infusions, electroconvulsive therapy and sleep deprivation. “Our goal is not to adopt any of these treatments for long-term use,” she says. “We’re trying to understand the biology of treatment action in order to increase our understanding of what depression is and how treatment works.”

The final component, Awareness and Hope, seeks to reduce the stigma of depression through understanding, partnership and outreach. Congdon is positive about the prospect of the DGC reducing the global burden of depression.

Adds Flint: “We don’t think of depression as being a single episode, and [then] that’s it — you’re free of the disorder. No. Everyone has a certain risk. Even if you come back with a clean bill of health, we’d still like to keep an eye on you.”

One patient, Roman, who participated in the fast-acting treatment study and received a dose of ketamine, has felt the stigma during a 40-year struggle with depression. “There is such guilt involved with depression, because there’s no X-ray, no blood test,” he says.

Roman is now depression free and optimistic. “Nobody ever killed themselves and felt hopeful at the same time,” he says. “There may not be a resolution to your challenges, but if you know there is a possibility of feeling relief, that knowledge itself is empowering.”